Biomedical Engineering Reference
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genotoxicity has been reported to date on pure silica particles, suggesting that the
cell nucleus is not reached by these particles.
Coming to the third point, related to the influence of silica solubility, it must
be admitted that it suffers from a lack of available data, although the impact of
soluble silica released during particle dissolution on cell viability is often men-
tioned. One reason is probably that silicic acid, Si(OH)
4
, the product of silica
dissolution, is a very reactive species that is very likely to combine with other com-
ponents of the biological environment, such as proteins.
2.3.3
In Vivo Toxicity and Biodistribution of Silica Particles
Most recent in vivo studies of silica nanoparticles concern intravenous injections in
mice. In the first time following injection, particles are found in the blood circulation
system. When a single infusion of plain particles with size ranging from 1,000 nm
to 30 nm was performed, an increase in the level of several proteins related to acute
inflammatory response (haptaglobin, C-reactive protein, serum amyloid A) was
observed. The intensity of this rise increases with decreasing particle size, so that
30 nm particles showed high toxicity, and was dose-dependent (Higashisaka et al.
2011
). Interaction of particles with blood circulation, as monitored by an increase in
mean arterial pressure and pulse arterial pressure, was also observed after repeated
infusions (Galagudza et al.
2010
). Noticeably, rapid (<15 min) animal death was also
reported when mesoporous particles were infused at high doses, a fact that may be
attributed to remaining toxic surfactants (Hudson et al.
2008
).
In a second step, particles circulate within the blood flow before being trans-
ported to organs. This can happen either due to the reticuloendothelial system (RES),
i.e. monocytes and macrophages that are responsible for the clearance of bacteria
and colloidal particles, or due to direct deposition. The first mechanism is related to
opsonization mechanisms in which specific serum proteins are adsorbed on the par-
ticle surface, triggering the macrophage response. The extent of this phenomenon
can be evaluated by two facts: (i) the blood circulation time and (ii) the favored
biodistribution of particles in specific organs (liver, spleen, lungs) where the RES is
particularly active (Burns et al.
2009
; Xie et al.
2010
). In the case of silica particles,
it was shown that they are found located within a few hours mainly in the liver, that
may suffer from noticeable injuries (Nishimori et al.
2009
; Galagudza et al.
2010
;
Kumar et al.
2010
; Souris et al.
2010
). However, depending on the nature of the
particle surface, they can also be found in spleen and lungs, and sometimes in skin.
Higher amounts of silica particles in these organs are found after 24 h but after 120 h
the particles are detected in stomach and intestine (Fig.
3
). After 360 h, nearly total
clearance was observed. Here again, the particle charge has a strong influence, as
positively-charged particle are found in urine and feces after 30 min whereas negatively-
charged colloids are still present in the gastrointestinal tract after 3 days.
It is worth noting that other internalization routes, such as intranasal, subcutaneous
and intraperitoneal, were also studied (Hudson et al.
2008
). Intranasal injections
showed very similar results compared to intravenous. Subcutaneous injections showed
very limited effects of silica particles whereas significant mortality was observed after
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